Many types of tumors, including glioma, melanoma, non-small cell lung, esophageal, head and neck cancer, among others, are intrinsically resistant to apoptosis induction and poorly responsive to current therapies with proapoptotic agents. In addition, tumors often develop multi-drug resistance based on the cellular efflux of chemotherapeutic agents. Thus, novel anticancer agents capable of overcoming these intrinsic or developed tumor resistance mechanisms are urgently needed. The present application covers a series of 2-aryl-2-(3-indolyl)acetohydroxamic acids, which are active against apoptosis- and multidrug-resistant cancer cells as well as glioblastoma stem-like cell cultures derived from patients. Thus, the described compounds serve as a novel chemical scaffold for the development of potentially highly effective clinical cancer drugs.
Apoptosis-resistant cancers represent a major challenge in the clinic as most of the currently available chemotherapeutic agents work through the induction of apoptosis and, therefore, provide limited therapeutic benefits for the patients affected by these malignancies. Cancers with such intrinsic resistance to proapoptotic stimuli include the tumors of the lung, liver, stomach, esophagus, pancreas as well as melanomas and gliomas. For example, patients afflicted by a type of gliomas, known as glioblastoma multiforme, have a median survival expectancy of less than 14 months when treated with a standard protocol of surgical resection, radiotherapy and chemotherapy with temozolomide, carmustine or cisplatin. Because glioma cells display resistance to apoptosis, they respond poorly to such conventional chemotherapy with proapoptotic agents.
Resistance to apoptosis is also an intrinsic property of tumor metastases. Successful treatment of metastases remains an important clinical challenge as 90% of cancer patients die from metastastic cancer spread. By acquiring resistance to anoikis, a cell death process resulting from the loss of contact with extracellular matrix or neighboring cells, metastatic cells display poor sensitivity to apoptosis induction and are thus poorly responsive to conventional proapoptotic chemotherapeutic agents. One solution to apoptosis resistance entails the complementation of cytotoxic therapeutic regimens with cytostatic agents, and thus a search for novel cytostatic anticancer drugs that can overcome cancer cell resistance to apoptosis is an important pursuit.
Often, tumors are initially susceptible to cancer agents and patients respond to chemotherapy but eventually experience a relapse in spite of the continuing treatment. In such instances of acquired resistance tumors generally become refractory to a broad spectrum of structurally and mechanistically diverse antitumor agents and this phenomenon is referred to as multidrug resistance (MDR). MDR usually results from upregulation of certain protein pumps, such as P-glycoprotein (P-gp) in cancer cells, causing a decreased intracellular drug concentration. MDR is a major factor that contributes to the failure of chemotherapy, for example with such widely used anticancer drugs as the vinca alkaloids or the taxanes.